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Hepatitis B Virus Infection
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Epidemiology

Hepatitis B virus (HBV) is the leading cause of chronic liver disease worldwide (960Lee WM. Hepatitis B virus infection. N Engl J Med 1997;337:1733-45., 961Levine OS, Vlahov D, Koehler J, et al. Seroepidemiology of hepatitis B virus in a population of injecting drug users: association with drug injection patterns. Am J Epidemiol 1995;142:331-41.). In countries with a low prevalence of endemic chronic HBV infection, HBV is transmitted primarily through sexual contact and injection-drug use, whereas perinatal and early childhood exposures are responsible for the majority of HBV transmission in high-prevalence countries. Although risk factors are similar, HBV is transmitted more efficiently than HIV (960Lee WM. Hepatitis B virus infection. N Engl J Med 1997;337:1733-45., 961Levine OS, Vlahov D, Koehler J, et al. Seroepidemiology of hepatitis B virus in a population of injecting drug users: association with drug injection patterns. Am J Epidemiol 1995;142:331-41., 962Beasley RP, Trepo C, Stevens CE, Szmuness W. The e antigen and vertical transmission of hepatitis B surface antigen. Am J Epidemiol 1977;105:94-8.). Up to 90% of HIV-infected persons have at least one serum marker of previous exposure to HBV (963Rodriguez-Mendez ML, Gonzalez-Quintela A, Aguilera A, Barrio E. Prevalence, patterns, and course of past hepatitis B virus infection in intravenous drug users with HIV-1 infection. Am J Gastroenterol 2000;95:1316-22., 964Scharschmidt BF, Held MJ, Hollander HH, et al. Hepatitis B in patients with HIV infection: relationship to AIDS and patient survival. Ann Intern Med 1992;117:837-8.), and approximately 10% have evidence of chronic hepatitis B (965Homann C, Krogsgaard K, Pedersen C, Andersson P, Nielsen JO. High incidence of hepatitis B infection and evolution of chronic hepatitis B infection in patients with advanced HIV infection. J Acquir Immune Defic Syndr 1991;4:416-20., 966Alter HJ, Seeff LB. Recovery, persistence, and sequelae in hepatitis C virus infection: a perspective on long-term outcome. Semin Liver Dis 2000;20:17-35., 967Bodsworth NJ, Cooper DA, Donovan B. The influence of human immunodeficiency virus type 1 infection on the development of the hepatitis B virus carrier state. J Infect Dis 1991;163:1138-40.). Several genotypes of HBV (A-H) have been identified and are geographically distributed. Genotype A is the most common among patients in the United States and Western Europe.

Clinical Manifestations

Most patients with acute or chronic HBV infection are asymptomatic or have nonspecific symptoms, such as fatigue. When present, symptoms of acute infection might include right upper quadrant abdominal pain, nausea, vomiting, fever, and arthralgias with or without jaundice.

Chronic HBV might lead to mild, moderate, or severe hepatitis with eventual development of cirrhosis and portal hypertension. The physical examination might be notable for signs of cirrhosis such as spider angiomata, palmar erythema, and signs of portal hypertension such as splenomegaly. Uncommon extrahepatic manifestations include polyarteritis nodosa, glomerulonephritis, and vasculitis. Without proper laboratory screening, HBV infection might not be clinically apparent until the onset of end-stage liver disease (ESLD), which is manifested as portal hypertension with ascites, variceal bleeding, coagulopathy, jaundice, or hepatic encephalopathy.

Hepatocellular carcinoma (HCC), which might complicate HBV infection before the onset of cirrhosis, is usually asymptomatic in its early stages. Patients with advanced HCC might experience abdominal pain, symptoms of liver failure, or ESLD, as previously described, or paraneoplastic syndromes (e.g., diarrhea, hypoglycemia, fever).

Diagnosis
Diagnosis of Infection and Disease with Serologic Testing

HIV-infected persons should be tested for HBV infection (789Cannon JS, Hamzeh F, Moore S, Nicholas J, Ambinder RF. Human herpesvirus 8-encoded thymidine kinase and phosphotransferase homologues confer sensitivity to ganciclovir. J Virol 1999;73:4786-93.). Initial testing for hepatitis B surface antigen (HBsAg), hepatitis B core antibody (anti-HBc total), and hepatitis B surface antibody (anti-HBs) should be performed because these will identify the majority of patients with chronic hepatitis B or who need vaccination to prevent infection. Certain specialists would test for HBsAg and anti-HBs only, excluding anti-HBc, as its presence or absence does not usually affect clinical practice. Chronic HBV infection is defined as a positive HBsAg and anti-HBc or a positive HBsAg, HBV DNA level, or hepatitis B e antigen (HBeAg) on two occasions at least 6 months apart.

Patients with chronic HBV infection should be tested for HBeAg, antibody to HBeAg (anti-HBe), and HBV DNA. Several tests for HBV DNA detection are available; however, the results are not interchangeable. Laboratories report either copies/mL or International Units (IU/mL). The latter is based upon a WHO standard and has greater interlaboratory reproducibility. HBV DNA levels are usually high in chronic infection. Patients with chronic HBeAg-positive infection tend to have higher levels of replicating virus than those with HBeAg-negative infection (108-1010 copies/mL of blood compared with 105-106copies/mL). Among HIV-uninfected adults with HBV monoinfection, high HBV DNA levels predict progression of liver disease, development of HCC, and lower responses to therapy. Data characterizing the predictive value in those with HIV/HBV coinfection are lacking.

Some patients test positive for anti-HBc alone, which might signify a false-positive result; exposure in the past with subsequent loss of anti-HBs; or "occult" HBV infection, which can be confirmed by detection of HBV DNA (968Grob P, Jilg W, Bornhak H, et al. Serological pattern "anti-HBc alone": report on a workshop. J Med Virol 2000;62:450-5., 969Hofer M, Joller-Jemelka HI, Grob PJ, Luthy R, Opravil M. Frequent chronic hepatitis B virus infection in HIV-infected patients positive for antibody to hepatitis B core antigen only. Eur J Clin Microbiol Infect Dis 1998;17:6-13.). The clinical significance of isolated anti-HBc is unknown (968Grob P, Jilg W, Bornhak H, et al. Serological pattern "anti-HBc alone": report on a workshop. J Med Virol 2000;62:450-5., 969Hofer M, Joller-Jemelka HI, Grob PJ, Luthy R, Opravil M. Frequent chronic hepatitis B virus infection in HIV-infected patients positive for antibody to hepatitis B core antigen only. Eur J Clin Microbiol Infect Dis 1998;17:6-13., 970Silva AE, McMahon BJ, Parkinson AJ, et al. Hepatitis B virus DNA in persons with isolated antibody to hepatitis B core antigen who subsequently received hepatitis B vaccine. Clin Infect Dis 1998;26:895-7., 971Lok AS, Lai CL, Wu PC. Prevalence of isolated antibody to hepatitis B core antigen in an area endemic for hepatitis B virus infection: implications in hepatitis B vaccination programs. Hepatology 1988;8:766-70.). HIV-infected patients have a higher frequency of isolated anti-HBc, particularly those patients with underlying hepatitis C virus (HCV) infection (972Gandhi RT, Wurcel A, Lee H, et al. Response to hepatitis B vaccine in HIV-1-positive subjects who test positive for isolated antibody to hepatitis B core antigen: implications for hepatitis B vaccine strategies. J Infect Dis 2005;191:1435-41.). The prevalence of HBV DNA in HIV-infected patients with isolated anti-HBc ranges from 1% to 45% (973Gandhi RT, Wurcel A, McGovern B, et al. Low prevalence of ongoing hepatitis B viremia in HIV-positive individuals with isolated antibody to hepatitis B core antigen. J Acquir Immune Defic Syndr 2003 34:439-41., 974Shire NJ, Sherman KE. Management of hepatitis B virus in HIV-positive patients. Minerva Gastroenterol Dietol 2006;52:67-87.), with most having low levels. Certain specialists recommend that HIV-infected persons with anti-HBc alone should be tested for HBV DNA before vaccination for HBV or before initiating ART because of the risk for reactivation of HBV and the occurrence of IRIS.

Diagnosis of Disease Progression and the Role of Liver Biopsy

Impairment of cellular immunity caused by HIV infection is associated with higher levels of hepatitis B viremia and lower viral clearance rates following acute HBV infection. Limited data indicate that HIV patients with chronic HBV infection are more likely to have detectable HBeAg (975Colin JF, Cazals-Hatem D, Loriot MA, et al. Influence of human immunodeficiency virus infection on chronic hepatitis B in homosexual men. Hepatology 1999;29:1306-10., 976Gilson RJ, Hawkins AE, Beecham MR, et al. Interactions between HIV and hepatitis B virus in homosexual men: effects on the natural history of infection. AIDS 1997;11:597-606.), lower rates of seroconversion, and an increased risk for liver-related mortality and morbidity (977Thio CL, Seaberg EC, Skolasky R, Jr., et al. HIV-1, hepatitis B virus, and risk of liver-related mortality in the Multicenter Cohort Study (MACS). Lancet 2002;360:1921-6.). Despite these differences, the pattern of disease progression is similar to that in monoinfected persons.

Liver biopsy with histologic examination remains a valuable tool for characterizing the activity and severity of chronic hepatitis B and might provide important information in monitoring disease progression and guiding treatment. However, the decision to perform a liver biopsy should be individualized based on the phase of chronic HBV as described below. Liver biopsies might result in major complications, such as excessive bleeding (<0.5%), bile peritonitis (0.09%), and, rarely, internal organ injury, although the overall mortality rate is fewer than 1 in 10,000 (978Van Thiel DH, Gavaler JS, Wright H, Tzakis A. Liver biopsy: its safety and complications as seen at a liver transplant center. Transplantation 1993;55:1087-90., 979Bravo AA, Sheth SG, Chopra S. Liver biopsy. N Engl J Med 2001;344:495-500.).

Patients with a diagnosis of chronic HBV infection who are not treated with antiviral agents should have a complete blood count, platelet count, alanine aminotransferase (ALT), albumin, prothrombin time, and bilirubin monitored at baseline and every 6 months to assess severity and progression of liver disease. Persistent low-level serum aminotransferase abnormalities might be associated with significant liver disease, although normal aminotransferases might also be seen in the setting of cirrhosis. Transient or persistent elevations in serum aminotransferase levels might occur before loss of HBeAg, on discontinuation of anti-HBV therapy, and in association with emergence of HBV drug resistance.

Patients who are HBe-Ag seropositive usually have high HBV DNA levels (>20,000 IU/mL) and abnormal levels of ALT. In some instances, increased levels of ALT might precede a decline in HBV DNA that is accompanied by the loss of HBeAg and development of anti-HBe. Seroconversion marks a transition from active disease to an inactive carrier state (980Lok AS, McMahon BJ. Chronic hepatitis B: update of recommendations. Hepatology 2004;39:857-61.). This transition can be spontaneous or associated with effective HBV treatment. Approximately 8%-12% of monoinfected patients spontaneously convert from a positive to a negative HBeAg and a positive anti-HBe per year (981Hoofnagle JH, Dusheiko GM, Seeff LB, et al. Seroconversion from hepatitis B e antigen to antibody in chronic type B hepatitis. Ann Intern Med 1981;94:744-8.). Spontaneous conversion rates in HIV-infected patients appear to be lower.

Although seroconversion usually implies transition to an inactive carrier state, the re-emergence of abnormal liver enzyme tests might reflect HBeAg-negative chronic hepatitis B disease. Although levels of HBV DNA are usually lower than in HBeAg-positive patients, HBeAg-negative patients experience an unrelenting but fluctuating course of disease progression, with viral loads usually ranging from 105 to 106 copies/mL (2 x 104-2 x 105 IU/mL), but they can be higher. Thus, in a patient without HBeAg, HBV DNA levels should still be measured. Liver biopsy is recommended in HBeAg-seronegative patients with detectable HBV DNA primarily for persons aged >40 years with "borderline" indications for treatment, such as those with minimally elevated ALT but high HBV DNA level (982Keeffe EB, Dieterich DT, Han SH, et al. A treatment algorithm for the management of chronic hepatitis B virus infection in the United States: an update. Clin Gastroenterol Hepatol 2006;4:936-62., 983Lok AS. Navigating the maze of hepatitis B treatments. Gastroenterology 2007;132:1586-94.).

Persons who acquire HBV infection perinatally have a high chance of becoming "immune tolerant," with normal aminotransferase levels despite the presence of high levels of HBV DNA. Such patients tend to have minimal disease and liver biopsy is usually not indicated; however, they tend to have HBeAg-positive chronic hepatitis B with elevated ALT levels later in life and remain at risk for the development of HCC, cirrhosis, and flares of hepatitis B (980Lok AS, McMahon BJ. Chronic hepatitis B: update of recommendations. Hepatology 2004;39:857-61.).

The inactive HBsAg carrier state is characterized by a negative HBeAg, normal ALT levels, and an HBV DNA level of <2,000-20,000 IU/mL (or 10,000-100,000 copies/mL). Liver biopsy is not recommended in patients who have cleared the virus (undetectable HBV DNA by PCR assay). However, although their prognosis is usually good, patients in the inactive carrier state remain at risk for reactivation of HBV and development of HCC, but the risk is lower than for those with active HBV replication. This is particularly true for those carriers who are older or who have cirrhosis or coinfection with HCV (984McMahon BJ. Epidemiology and natural history of hepatitis B. Semin Liver Dis 2005;25(Suppl 1):3-8., 985Fattovich G, McIntyre G, Thursz M, et al. Hepatitis B virus precore/core variation and interferon therapy. Hepatology 1995;22:1355-62., 986Zacharakis GH, Koskinas J, Kotsiou S, et al. Natural history of chronic HBV infection: a cohort study with up to 12 years follow-up in North Greece (part of the Interreg I-II/EC-project). J Med Virol 2005;77:173-9., 987Yang SS, Cheng KS, Lai YC, et al. Decreasing serum alpha-fetoprotein levels in predicting poor prognosis of acute hepatic failure in patients with chronic hepatitis B. J Gastroenterol 2002;37:626-32.).

Reactivation of HBV, spontaneous or related to chemotherapy or immunosuppression, can lead to substantial hepatic flares and necroinflammatory liver disease (988Zllner B, Feucht HH, Sterneck M, et al. Clinical reactivation after liver transplantation with an unusual minor strain of hepatitis B virus in an occult carrier. Liver Transpl 2006;12:1283-9., 990Dai MS, Wu PF, Shyu RY, Lu JJ, Chao TY. Hepatitis B virus reactivation in breast cancer patients undergoing cytotoxic chemotherapy and the role of preemptive lamivudine administration. Liver Int 2004;24:540-6., 991Keeffe EB. Hepatitis B virus reactivation with chemotherapy: diagnosis and prevention with antiviral prophylaxis. Rev Gastroenterol Disord 2004;4:46-8.). Although reactivation of HBV can be associated with flares in serum aminotransferases, other etiologies for increased aminotransferase levels, such as hepatotoxicity from ARVs or other drugs or acquisition of another hepatitis virus infection such as hepatitis A, C, or hepatitis delta virus (HDV), must be ruled out (992Altfeld M, Rockstroh JK, Addo M, et al. Reactivation of hepatitis B in a long-term anti-HBs-positive patient with AIDS following lamivudine withdrawal. J Hepatol 1998;29:306-9., 993Bessesen M, Ives D, Condreay L, Lawrence S, Sherman KE. Chronic active hepatitis B exacerbations in human immunodeficiency virus-infected patients following development of resistance to or withdrawal of lamivudine. Clin Infect Dis 1999;28:1032-5., 994Perrillo RP. Acute flares in chronic hepatitis B: the natural and unnatural history of an immunologically mediated liver disease. Gastroenterology 2001;120:1009-22., 995Sulkowski MS, Thomas DL, Chaisson RE, Moore RD. Elevated liver enzymes following initiation of antiretroviral therapy. JAMA 2000;283:2526-7.).

Patients with chronic hepatitis B are at increased risk for HCC. Among HIV-coinfected persons, who might have an even higher risk for HBV-related HCC than HBV monoinfected patients, monitoring alpha fetoprotein (AFP) level and ultrasound of the liver every 6 months (996Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology 2001;34:1225-41.) might be recommended; however, the effectiveness of this screening strategy has not been studied in this population, and the optimal HCC screening method and interval are not known (997Salmon-Ceron D, Lewden C, Morlat P, et al. Liver disease as a major cause of death among HIV infected patients: role of hepatitis C and B viruses and alcohol. J Hepatol 2005;42:799-805., 998Bruno R, Sacchi P, Filice C, Puoti M, Filice G. Hepatocellular carcinoma in HIV-infected patients with chronic hepatitis: an emerging issue. J Acquir Immune Defic Syndr 2002;30:535-6., 999Weber R, Sabin CA, Friis-Moller N, et al. Liver-related deaths in persons infected with the human immunodeficiency virus: the D:A:D study. Arch Intern Med 2006;166:1632-41.).

Preventing Exposure

HIV-infected persons should be counseled about the risk for household, sexual, and needle-sharing transmission of HBV; the avoidance of behaviors associated with such transmission; and the need for any such susceptible contacts to receive hepatitis A and B vaccine as described below. As drug injection via contaminated syringes previously used by infected persons is the primary route of HBV transmission among IDUs, they should be encouraged to stop using injection drugs, preferably by entering a substance abuse treatment program (AII). If IDUs are unwilling or unable to discontinue the use of injection drugs, they should be advised not to share needles or drug preparation equipment to reduce the risk for transmission of HBV infection (BII). Access to sterile injection equipment may be facilitated through enrollment of IDUs in needle exchange programs (NEPs) (1000Vlahov D, Junge B, Brookmeyer R, et al. Reductions in high-risk drug use behaviors among participants in the Baltimore needle exchange program. J Acquir Immune Defic Syndr Hum Retrovirol 1997;16:400-6., 1001Hagan H, Jarlais DC, Friedman SR, Purchase D, Alter MJ. Reduced risk of hepatitis B and hepatitis C among injection drug users in the Tacoma syringe exchange program. Am J Public Health 1995;85:1531-7., 1002Hagan H, McGough JP, Thiede H, et al. Syringe exchange and risk of infection with hepatitis B and C viruses. Am J Epidemiol 1999;149:203-13.).

Persons considering tattooing or body-piercing should be informed of potential risks of acquiring HBV, which could be transmitted if equipment is not sterile or if proper infection control procedures are not followed (AIII).

Safe-sex practices should be encouraged for all HIV-infected persons; barrier precautions (e.g., latex condoms) are recommended to reduce the risk for exposure to sexually transmitted pathogens, including HBV (AII).

Preventing Disease

HIV-infected patients who do not have evidence of previous exposure to HBV should be vaccinated with hepatitis B vaccine (AII). Given the decreased response rate to the vaccine in the setting of HIV infection, all HIV-infected patients should have anti-HBs titers obtained 1 month after completion of the vaccine series to document response (BIII). If no response is observed, revaccination should be considered (BIII). HBV vaccination is safe in HIV-infected patients. Transient increases in HIV RNA have been reported after HBV vaccination but do not appear to have clinical relevance (1003Fonseca MO, Pang LW, de Paula Cavalheiro N, Barone AA, Heloisa Lopes M. Randomized trial of recombinant hepatitis B vaccine in HIV-infected adult patients comparing a standard dose to a double dose. Vaccine 2005;23:2902-8., 1004Rey D, Krantz V, Partisani M, et al. Increasing the number of hepatitis B vaccine injections augments anti-HBs response rate in HIV-infected patients: effects on HIV-1 viral load. Vaccine 2000;18:1161-5., 1005Veiga AP, Casseb J, Duarte AJ. Humoral response to hepatitis B vaccination and its relationship with T CD45RA+ (naive) and CD45RO+ (memory) subsets in HIV-1-infected subjects. Vaccine 2006;24:7124-8.).

A patient who is seropositive for anti-HBc and anti-HBs has resolved infection and does not need vaccination. However, reactivation of HBV has been observed in immunosuppressed patients. The presence of anti-HBs alone at levels of >10 IU/mL is consistent with seroprotection, usually from vaccination (1006Hadler SC, Francis DP, Maynard JE, et al. Long-term immunogenicity and efficacy of hepatitis B vaccine in homosexual men. N Engl J Med 1986;315:209-14.), and no further vaccinations are required.

Determining whether hepatitis B vaccine should be administered to patients with "isolated" anti-HBc is not clear because, in addition to a false-positive result, this pattern might signify exposure in the distant past with subsequent loss of anti-HBs or more rarely, occult HBV (1007McMahon D, Winkelstein A, Huang XL, et al. Acute reactions associated with the infusion of ampligen. AIDS 1992;6:235-6.). One approach in this setting is to administer one dose of hepatitis B vaccine followed in 2 weeks by anti-HBs testing to determine if an anamnestic response occurs, although the overall response rate described in previous studies is low (16%) (973Gandhi RT, Wurcel A, McGovern B, et al. Low prevalence of ongoing hepatitis B viremia in HIV-positive individuals with isolated antibody to hepatitis B core antigen. J Acquir Immune Defic Syndr 2003 34:439-41., 1008Al-Mekhaizeem KA, Miriello M, Sherker AH. The frequency and significance of isolated hepatitis B core antibody and the suggested management of patients. CMAJ 2001;165:1063-4., 1009Jongjirawisan Y, Ungulkraiwit P, Sungkanuparph S. Isolated antibody to hepatitis B core antigen in HIV-1 infected patients and a pilot study of vaccination to determine the anamnestic response. J Med Assoc Thai 2006;89:2028-34.). Larger studies in HIV-uninfected persons with isolated anti-HBc demonstrate that most persons mount a slow, or primary, rather than a rapid, or anamnestic, response after vaccination (1007McMahon D, Winkelstein A, Huang XL, et al. Acute reactions associated with the infusion of ampligen. AIDS 1992;6:235-6.). The majority of HIV-infected patients with isolated anti-HBc are not immune to HBV infection and should be vaccinated with a complete primary series of hepatitis B vaccine (BII) (973Gandhi RT, Wurcel A, McGovern B, et al. Low prevalence of ongoing hepatitis B viremia in HIV-positive individuals with isolated antibody to hepatitis B core antigen. J Acquir Immune Defic Syndr 2003 34:439-41., 1009Jongjirawisan Y, Ungulkraiwit P, Sungkanuparph S. Isolated antibody to hepatitis B core antigen in HIV-1 infected patients and a pilot study of vaccination to determine the anamnestic response. J Med Assoc Thai 2006;89:2028-34.). Certain specialists would test for HBV DNA to rule out occult chronic HBV infection before administering a complete primary series of hepatitis B vaccine.

The immunogenicity of hepatitis B vaccination in HIV-infected adults is 18%-72% (974Shire NJ, Sherman KE. Management of hepatitis B virus in HIV-positive patients. Minerva Gastroenterol Dietol 2006;52:67-87.) and is lower than in HIV-seronegative healthy adults, in whom seroconversion rates are >90% (1010Mast EE, Weinbaum CM, Fiore AE, et al. A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2006;55(No. RR-16).). Compared with HIV-seronegative healthy adults, HIV-seropositive patients also have lower mean antibody titers and have faster declines of protective antibody over time (1004Rey D, Krantz V, Partisani M, et al. Increasing the number of hepatitis B vaccine injections augments anti-HBs response rate in HIV-infected patients: effects on HIV-1 viral load. Vaccine 2000;18:1161-5., 1011Loke RH, Murray-Lyon IM, Coleman JC, Evans BA, Zuckerman AJ. Diminished response to recombinant hepatitis B vaccine in homosexual men with HIV antibody: an indicator of poor prognosis. J Med Virol 1990;31:109-11., 1012Tayal SC, Sankar KN. Impaired response to recombinant hepatitis B vaccine in asymptomatic HIV-infected individuals. AIDS 1994;8:558-9.). The negative impact of low CD4+ counts on hepatitis B vaccine responses has been a consistent finding across several studies (1003Fonseca MO, Pang LW, de Paula Cavalheiro N, Barone AA, Heloisa Lopes M. Randomized trial of recombinant hepatitis B vaccine in HIV-infected adult patients comparing a standard dose to a double dose. Vaccine 2005;23:2902-8., 1004Rey D, Krantz V, Partisani M, et al. Increasing the number of hepatitis B vaccine injections augments anti-HBs response rate in HIV-infected patients: effects on HIV-1 viral load. Vaccine 2000;18:1161-5., 1005Veiga AP, Casseb J, Duarte AJ. Humoral response to hepatitis B vaccination and its relationship with T CD45RA+ (naive) and CD45RO+ (memory) subsets in HIV-1-infected subjects. Vaccine 2006;24:7124-8., 1013Bruguera M, Cremades M, Salinas R, et al. Impaired response to recombinant hepatitis B vaccine in HIV-infected persons. J Clin Gastroenterol 1992;14:27-30., 1014Keet IP, van Doornum G, Safary A, Coutinho RA. Insufficient response to hepatitis B vaccination in HIV-positive homosexual men. AIDS 1992;6:509-10., 1016Tedaldi EM, Baker RK, Moorman AC, et al. Hepatitis A and B vaccination practices for ambulatory patients infected with HIV. Clin Infect Dis 2004;38:1478-84.). Other factors associated with lower seroconversion rates include the presence of detectable HIV RNA (1005Veiga AP, Casseb J, Duarte AJ. Humoral response to hepatitis B vaccination and its relationship with T CD45RA+ (naive) and CD45RO+ (memory) subsets in HIV-1-infected subjects. Vaccine 2006;24:7124-8., 1016Tedaldi EM, Baker RK, Moorman AC, et al. Hepatitis A and B vaccination practices for ambulatory patients infected with HIV. Clin Infect Dis 2004;38:1478-84., 1017Overton ET, Sungkanuparph S, Powderly WG, et al. Undetectable plasma HIV RNA load predicts success after hepatitis B vaccination in HIV-infected persons. Clin Infect Dis 2005;41:1045-8.), coinfection with HCV, occult hepatitis B infection, and the general health status of the host (973Gandhi RT, Wurcel A, McGovern B, et al. Low prevalence of ongoing hepatitis B viremia in HIV-positive individuals with isolated antibody to hepatitis B core antigen. J Acquir Immune Defic Syndr 2003 34:439-41., 1018Lee SD, Chan CY, Yu MI, et al. Hepatitis B vaccination in patients with chronic hepatitis C. Med Virol 1999;59:463-8., 1019Wiedmann M, Liebert UG, Oesen U, et al. Decreased immunogenicity of recombinant hepatitis B vaccine in chronic hepatitis C. Hepatology 2000;31:230-4.,1020Anthony DD, Yonkers NL, Post AB, et al. Selective impairments in dendritic cell-associated function distinguish hepatitis C virus and HIV infection. J Immunol 2004;172:4907-16., 1021Sarobe P, Lasarte JJ, Casares N, et al. Abnormal priming of CD4+ T cells by dendritic cells expressing hepatitis C virus core and E1 proteins. J Virol 2002;76:5062-70., 1022Auffermann-Gretzinger S, Keeffe EB, Levy S. Impaired dendritic cell maturation in patients with chronic, but not resolved, hepatitis C virus infection. Blood 2001;97:3171-6., 1023Shire NJ, Rouster SD, Rajicic N, Sherman KE. Occult hepatitis B in HIV-infected patients. J Acquir Immune Defic Syndr 2004;36:869-75.).

Several novel approaches have been investigated to improve primary vaccine responses and those among vaccine nonresponders. These have included increasing the dosage of vaccine (1003Fonseca MO, Pang LW, de Paula Cavalheiro N, Barone AA, Heloisa Lopes M. Randomized trial of recombinant hepatitis B vaccine in HIV-infected adult patients comparing a standard dose to a double dose. Vaccine 2005;23:2902-8., 1005Veiga AP, Casseb J, Duarte AJ. Humoral response to hepatitis B vaccination and its relationship with T CD45RA+ (naive) and CD45RO+ (memory) subsets in HIV-1-infected subjects. Vaccine 2006;24:7124-8.), the number of doses (1004Rey D, Krantz V, Partisani M, et al. Increasing the number of hepatitis B vaccine injections augments anti-HBs response rate in HIV-infected patients: effects on HIV-1 viral load. Vaccine 2000;18:1161-5.), or use of adjuvant immunostimulatory molecules (1024Cooper CL, Davis HL, Angel JB, et al. CPG 7909 adjuvant improves hepatitis B virus vaccine seroprotection in antiretroviral-treated HIV-infected adults. AIDS 2005;19:1473-9.). One double-blind, randomized controlled trial that compared the use of a standard dose (20 mcg) with a double dose (40 mcg) of recombinant hepatitis B vaccine in 210 previously unvaccinated HIV-infected patients demonstrated a substantially higher seroconversion rate with use of the double dose of vaccine, but only in the subgroup of patients with CD4+ counts >350 cells/µL (1003Fonseca MO, Pang LW, de Paula Cavalheiro N, Barone AA, Heloisa Lopes M. Randomized trial of recombinant hepatitis B vaccine in HIV-infected adult patients comparing a standard dose to a double dose. Vaccine 2005;23:2902-8.). In one study of 32 HIV-infected patients, administration of 1 additional vaccine dose increased the proportion of responders only marginally; however, a sixfold increase in geometric mean titers was demonstrated among those who did respond (1014Keet IP, van Doornum G, Safary A, Coutinho RA. Insufficient response to hepatitis B vaccination in HIV-positive homosexual men. AIDS 1992;6:509-10.). Doubling the number of vaccine doses in nine HIV-infected patients who did not initially respond to a hepatitis B vaccination series led to protective surface antibody levels in seven persons (1004Rey D, Krantz V, Partisani M, et al. Increasing the number of hepatitis B vaccine injections augments anti-HBs response rate in HIV-infected patients: effects on HIV-1 viral load. Vaccine 2000;18:1161-5.).

On the basis of these data, early vaccination is recommended in HIV-infected patients before the CD4+ count declines to <350 cells/µL (AII) (1014Keet IP, van Doornum G, Safary A, Coutinho RA. Insufficient response to hepatitis B vaccination in HIV-positive homosexual men. AIDS 1992;6:509-10., 1025Collier AC, Corey L, Murphy VL, Handsfield HH. Antibody to human immunodeficiency virus (HIV) and suboptimal response to hepatitis B vaccination. Ann Intern Med 1988;109:101-5.). However, vaccination should not be deferred for those with negative or indeterminate serologies while awaiting a rise in CD4+ count to >350 cells/µL. Because some HIV-infected patients with CD4+ counts <200 cells/µL do respond to vaccination, vaccination should be performed as previously recommended (AII), with testing for anti-HBs 1 month after completion of the series (BIII). If no response occurs, revaccination should be considered (BIII). Certain specialists might delay revaccination until after a sustained increase in CD4+ count is achieved on ART.

One study has suggested that HIV-infected persons with a CD4+ count >350 cells/µL had improved responses when vaccinated with 40 mcg of HBV vaccine on a 0-, 1-, and 6-month schedule (1003Fonseca MO, Pang LW, de Paula Cavalheiro N, Barone AA, Heloisa Lopes M. Randomized trial of recombinant hepatitis B vaccine in HIV-infected adult patients comparing a standard dose to a double dose. Vaccine 2005;23:2902-8.). Thus, certain specialists recommend initial hepatitis B vaccination in any HIV-infected person with 40 mcg doses of either vaccine at the recommended intervals (CIII). Additional studies are needed to determine optimal vaccination strategies in patients with advanced immunosuppression. ART should be optimized to attain complete suppression of HIV replication and increased CD4+ count, as these factors have been associated with better antibody responses to HBV vaccination (CIII). Trials of immunomodulatory agents to improve HBV vaccine responses have led to mixed results, and data are currently insufficient to warrant a recommendation favoring their use (CIII).

No vaccination strategy has been consistently effective or adequately studied in vaccine nonresponders. For patients who have not attained an anti-HBs level >10 IU/mL after completion of a primary vaccine series, a second vaccine series is recommended (BIII). Certain specialists recommend that in such cases, revaccination with 40 mcg doses of either of the available vaccines be considered, regardless of which dose was used initially (CIII). Anti-HBs should be obtained approximately 1 month after completion of the vaccine series to assess vaccine response (BIII) (1025Collier AC, Corey L, Murphy VL, Handsfield HH. Antibody to human immunodeficiency virus (HIV) and suboptimal response to hepatitis B vaccination. Ann Intern Med 1988;109:101-5.). Certain specialists suggest once yearly evaluations for patients who have an ongoing risk for HBV acquisition (CIII), as recommended for dialysis patients (1026Bailey DN. Effect of coadministered drugs and ethanol on the binding of therapeutic drugs to human serum in vitro. Ther Drug Monit 2001;23:71-4.). This is particularly important in patients who have a low level of protective antibody, because loss of antibody over time is related to the maximal antibody response after vaccination, and loss of antibody among dialysis patients has translated into loss of protection against HBV infection (1006Hadler SC, Francis DP, Maynard JE, et al. Long-term immunogenicity and efficacy of hepatitis B vaccine in homosexual men. N Engl J Med 1986;315:209-14., 1027Mannucci PM, Zanetti AR, Gringeri A, et al. Long-term immunogenicity of a plasma-derived hepatitis B vaccine in HIV seropositive and HIV seronegative hemophiliacs. Arch Intern Med 1989;149:1333-7., 1028Ahuja TS, Abbott KC, Pack L, Kuo YF. HIV-associated nephropathy and end-stage renal disease in children in the United States. Pediatr Nephrol 2004;19:808-11.). Immune-competent hepatitis B vaccine responders, however, remain protected against the development of clinical disease and chronic HBV infection despite subsequent declines in anti-HBs to <10 IU/mL (1027Mannucci PM, Zanetti AR, Gringeri A, et al. Long-term immunogenicity of a plasma-derived hepatitis B vaccine in HIV seropositive and HIV seronegative hemophiliacs. Arch Intern Med 1989;149:1333-7., 1029Mast EE, Hwang LY, Seto DS, et al. Risk factors for perinatal transmission of hepatitis C virus (HCV) and the natural history of HCV infection acquired in infancy. J Infect Dis 2005;192:1880-9.).

Hepatitis A vaccination is recommended in persons with chronic liver disease, MSM, and IDUs (529CDC. Workowski KA, Berman SM: Sexually transmitted diseases treatment guidelines. MMWR 2006;55(No. RR-11)., 1030CDC. Prevention of hepatitis A through active or passive immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2006;55(No. RR-7).). HAV-susceptible, HIV-infected persons with risk factors for HAV infection should receive hepatitis A vaccination (AII). As with hepatitis B vaccination, the response to hepatitis A vaccination is reduced in those with CD4+ counts <200 cells/µL. Certain specialists might delay hepatitis A vaccination until the CD4+ count is >200 cells/µL on ART (CIII). Antibody response should be assessed 1 month after vaccination; nonresponders should be revaccinated (BIII).

Treatment of Disease

Patients with chronic hepatitis B disease should be advised to avoid or limit alcohol consumption because of its effects on the liver (AIII). In addition, they should be counseled about the risk for household, sexual, and needle-sharing transmission and the need for any such susceptible contacts to receive hepatitis A and B vaccine as described above.

The goals of anti-HBV therapy are to prevent disease progression and reduce HBV-related morbidity and mortality. Treated patients rarely become HBsAg negative because HBV reservoirs generally are not sufficiently reduced by available anti-HBV therapy. HBV might persist in the liver, in the absence of circulating virus, as closed circular DNA (ccDNA), which can lead to reactivation after chemotherapy, steroid use, or immunosuppression, including HIV-associated immunosuppression. Nevertheless, studies in HBV-monoinfected patients suggest suppression of HBV DNA to a "nonreplicative" state, HBeAg seroconversion from positive to negative, seroconversion to anti-HBe, loss of HBsAg, and acquisition of anti-HBs are all associated with decreased incidence of HCC and improved survival; thus, these surrogates also are goals of anti-HBV treatment for HIV-infected persons. For HBeAg-negative patients with increased ALT and HBV DNA levels, long-term antiviral suppression might be indicated because treatment discontinuation has been associated with virologic relapse.

In HIV/HBV-coinfected patients, the imperative to treat depends not only on the level of HBV viremia and degree of biochemical and/or histologic disease, but also on whether the patient is initiating ART. HIV/HBV-coinfected patients initiating ART should be treated for HBV, regardless of the level of HBV DNA, either with antiviral agents active against both HIV and HBV or with antiviral agents with independent activity against each virus (CIII). This approach might reduce the risk for IRIS, particularly in those who have advanced immunodeficiency. If ART is not required, then initiation of treatment for HBV is the same as for HBV-monoinfected patients. Anti-HBV therapy is indicated for persons with abnormal ALT levels and HBV DNA levels >20,000 IU/mL (>105 copies per mL) for HBeAg-positive patients, and abnormal ALT levels with HBV DNA levels >2,000 IU/mL (>104 copies per mL) for HBeAg-negative patients (CIII). However, because of the increased rate of liver disease progression in the setting of HIV infection, certain specialists recommend treatment at any level of detectable HBV DNA, especially in the setting of elevated ALT levels (CIII). In addition, anti-HBV treatment should be considered for HIV-infected patients with low but detectable HBV DNA levels who have substantial histologic inflammatory activity or fibrosis on liver biopsy (CIII). Certain specialists recommend treatment of those with advanced fibrosis or cirrhosis on liver biopsy with any detectable HBV DNA level, provided other causes for chronic liver disease have been eliminated (1031Soriano V, Puoti M, Bonacini M, et al. Care of patients with chronic hepatitis B and HIV co-infection: recommendations from an HIV-HBV International Panel. AIDS 2005;19:221-40.).

Treatment options for HBV in the setting of HIV infection must consider the goals of therapy and the effect treatment might have on both HIV and HBV replication. FDA-approved antiviral drugs available for treatment of HBV infection include lamivudine, adefovir, entecavir, tenofovir, standard interferon-alfa, pegylated interferon (pegIFN)-alfa, and telbivudine. FDA-approved HIV antiretroviral medications, such as emtricitabine (and its single-pill combination with tenofovir), also have substantial activity against HBV, although they are not approved for this indication.

IFN-alfa-2a and -2b, administered in subcutaneous doses of 5 MU daily or 10 MU three times per week, are approved for the treatment of chronic hepatitis B disease among HIV-uninfected persons, but not among HIV-infected patients. Approximately one-third of HIV-seronegative patients will clear HBeAg with either of these IFN regimens (996Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology 2001;34:1225-41., 1032Wong DK, Yim C, Naylor CD, et al. Interferon alfa treatment of chronic hepatitis B: randomized trial in a predominantly homosexual male population. Gastroenterology 1995;108:165-71.), and the response is sustained among 80%-90% of persons followed for 4-8 years (1033Krogsgaard K. The long-term effect of treatment with interferon-alpha 2a in chronic hepatitis B. J Viral Hepat 1998;5:389-97.). PegIFN alfa-2a is also approved for treatment of HBV among HIV-seronegative patients and in clinical trials was proven to be superior to standard IFN for both HBeAg-positive and HBeAg-negative patients when used for 48 weeks (1034Marcellin P, Lau GK, Bonino F, et al. Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B. N Engl J Med 2004;351:1206-17., 1035Lau GK, Piratvisuth T, Luo KX, et al. Peginterferon alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B. N Engl J Med 2005;352:2682-95.). No published data exist regarding efficacy of either formulation of pegIFN in the setting of HIV/HBV coinfection. Although HIV replication can be suppressed by pegIFN alfa (1036Torriani FJ, Rodriguez-Torres M, Rockstroh JK, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients. N Engl J Med 2004;351:438-50.), no evidence indicates that IFN selects for resistance mutations that will influence future therapeutic options for HIV infection. On the basis of this information, pegIFN alfa-2a might be considered for treatment of HBV infection in HIV-coinfected patients irrespective of the need for ART for treatment of their HIV infection (CIII).

Among HIV-uninfected persons, the response rates to lamivudine-containing regimens are >50% in patients with ALT levels >5 times the ULN and 20%-35% among patients with ALT levels 2-5 times the ULN. Lamivudine is active against hepatitis B and HIV at the 150 mg twice-daily dose used for treatment of HIV infection. HBeAg seroconversion rates appear to be low in HIV-infected patients treated with this agent. Resistance to lamivudine occurs in the majority of patients on chronic therapy; the rates of resistance appear to be even higher in patients with HIV infection (1037Benhamou Y, Bochet M, Thibault V, et al. Long-term incidence of hepatitis B virus resistance to lamivudine in human immunodeficiency virus-infected patients. Hepatology 1999;30:1302-6.). Because lamivudine is active against both HBV and HIV and monotherapy for HBV will select for HIV resistance mutations, lamivudine should not be used for treatment of HBV in HIV-infected patients who are not also being treated with combination ART for their HIV infection (EIII).

Emtricitabine is active against HBV and HIV. Because of its structural similarities to lamivudine, emtricitabine also is associated with a relatively rapid onset of HBV and HIV drug resistance, and cross resistance of HIV and HBVto lamivudine also should be assumed in patients with suspected lamivudine resistance. As with lamivudine, emtricitabine should not be used for treatment of HBV in coinfected patients who are not being treated with combination ART for their HIV infection (EIII).

Adefovir is effective in both HBeAg-positive and HBeAg-negative patients with chronic HBV infection, although viral suppression occurs at a slower rate than with other agents and rates of seroconversion are low. Despite the slower viral load decline, the onset of drug resistance to adefovir is delayed compared with lamivudine or emtricitabine. The addition of adefovir to lamivudine in HIV/HBV-coinfected patients with HBV lamivudine resistance has been associated with an approximately 4-log10 decline in HBV viremia (1038Benhamou Y, Thibault V, Vig P, et al. Safety and efficacy of adefovir dipivoxil in patients infected with lamivudine-resistant hepatitis B and HIV-1. J Hepatol 2006;44:62-7.). During 4 years of treatment, 25% of patients in one study attained complete virologic suppression. In those with detectable HBV viremia, no adefovir-associated mutations were observed. In coinfected patients, initial reports suggested that adefovir dipivoxil might be associated with selection of HIV-associated mutations (K65R and K70E) (1039Mulato AS, Lamy PD, Miller MD, et al. Genotypic and phenotypic characterization of human immunodeficiency virus type 1 variants isolated from AIDS patients after prolonged adefovir dipivoxil therapy. Antimicrob Agents Chemother 1998;42:1620-8.). However, additional studies have not demonstrated selection of these mutations after up to 4 years of therapy, although minority variants could have been missed (1040Sheldon JA, Corral A, Rods B, et al. Risk of selecting K65R in antiretroviral-naive HIV-infected individuals with chronic hepatitis B treated with adefovir. AIDS 2005;19:2036-8.). On the basis of these data, adefovir might be considered for treatment of HBV in HIV-coinfected patients, irrespective of the need for their HIV infection. (CIII).

Tenofovir, 300 mg daily, is more potent in vitro than adefovir, 10 mg daily, against HBV and data from human clinical trials and clinical experience indicate it is also active against lamivudine-resistant and wild-type HBV. A prospective, randomized, double-blind, placebo-controlled, noninferiority trial comparing tenofovir to adefovir in HIV-infected patients demonstrated benefit of tenofovir in the setting of lamivudine-resistant HBV (1041Peters MG, Andersen J, Lynch P, et al. Randomized controlled study of tenofovir and adefovir in chronic hepatitis B virus and HIV infection: ACTG A5127. Hepatology 2006;44:1110-6.). Two recent randomized, double-blind studies, one with HBeAg-negative and another with HBeAg-positive patients, demonstrated the superiority of tenofovir over adefovir related to HBV DNA suppression in HBV-monoinfected patients (1042Chen CH, Lee CM, Hung CH, et al. Clinical significance and evolution of core promoter and precore mutations in HBeAg-positive patients with HBV genotype B and C: a longitudinal study. Liver Int 2007;27:806-15., 1043Keeffe EB, Marcellin P. New and emerging treatment of chronic hepatitis B. Clin Gastroenterol Hepatol 2007;5:285-94.). As with lamivudine and emtricitabine, tenofovir should not be used for treatment of HBV in HIV-coinfected patients who are not receiving combination ART for treatment of their HIV infection because of the risk for acquiring HIV-associated resistance mutations (EII).

Entecavir is approved for treatment of HBV and in clinical trials was proven to be more effective than lamivudine with regard to the rate of HBV DNA decline and viral suppression at 48 weeks of treatment. Of the available agents for treatment of HBV other than interferon, entecavir is associated with the slowest onset of resistance, which usually requires a background of mutations at M204V/I and L180M to emerge. Literature in HIV/HBV coinfection is limited, but in a trial of 68 coinfected, lamivudine-experienced patients who were randomly assigned to receive either entecavir or continue on lamivudine monotherapy, a >3-log10 decline in HBV DNA was noted in the entecavir arm versus the lamivudine arm. No change in HIV RNA levels occurred although these patients were on effective HIV therapy. However, a recent report described three patients who experienced an approximately 1-log10 drop in HIV RNA with initiation of entecavir monotherapy (1044McMahon MA, Jilek BL, Brennan TP, et al. The HBV drug entecavireffects on HIV-1 replication and resistance. N Engl J Med 2007;356:2614-21.). In addition, one patient who had received lamivudine in the past developed an HIV-associated mutation (M184V) during monotherapy with entecavir. A case report of the M184V emerging in a treatment-naïve patient on entecavir monotherapy also has been reported (1045Matthews GV, Dore GJ. Combination of tenofovir and lamivudine versus tenofovir after lamivudine failure for therapy of hepatitis B in HIV-coinfection. AIDS 2007;21:777-8.). An FDA warning is available at http://www.fda.gov/medwatch/safety/2007/Baraclude_DHCP_02-2007.pdf. On the basis of this information, entecavir should not be used as monotherapy for treatment of HBV in HIV-coinfected patients who are not also receiving combination ART for treatment of their HIV infection because of the risk for developing HIV-associated resistance mutations (EII).

Telbivudine has demonstrated efficacy in patients with HBeAg-positive and HBeAg-negative infection and is FDA approved for treatment of chronic HBV infection (1046Chan HL, Heathcote EJ, Marcellin P, et al. Treatment of hepatitis B e antigen positive chronic hepatitis with telbivudine or adefovir: a randomized trial. Ann Intern Med 2007;147:745-54., 1047Lai CL, Leung N, Teo EK, et al. A 1-year trial of telbivudine, lamivudine, and the combination in patients with hepatitis B e antigen-positive chronic hepatitis B. Gastroenterology 2005;129:528-36.). It is well tolerated, but like lamivudine, emergence of HBV resistance over time is common. Telbivudine is not active against lamivudine-resistant HBV. Therefore, telbivudine monotherapy is not recommended (DII). No clinical data are currently available in HIV/HBV-coinfected patients, but studies are in progress.

Famciclovir is less active than lamivudine against HBV and is not active in lamivudine-resistant HBV; therefore, its use is not recommended (DII) (1048Matthews GV, Pillay D, Cane P, et al. Failure of combination therapy with lamivudine and famciclovir following lamivudine monotherapy for hepatitis B virus infection in patients coinfected with human immunodeficiency virus-1. Clin Infect Dis 2001;33:2049-54., 1049Rayes N, Seehofer D, Hopf U, et al. Comparison of famciclovir and lamivudine in the long-term treatment of hepatitis B infection after liver transplantation. Transplantation 2001;71:96-101., 1050de Man RA, Marcellin P, Habal F, et al. A randomized, placebo-controlled study to evaluate the efficacy of 12-month famciclovir treatment in patients with chronic hepatitis B e antigen-positive hepatitis B. Hepatology 2000;32:413-7.).

Treatment of HBV in HIV-Infected Patients Who Are Receiving ART

Current guidelines recommend ART for HIV-infected patients who require treatment for HBV infection, regardless of CD4+ count. In such patients, simplifying the treatment regimen can be achieved by offering at least two agents with dual activity against HIV and HBV, considering that a third agent is also required for effective treatment of HIV. Chronic administration of lamivudine as the only active drug against HBV leads to a high rate of HBV drug resistance because of key mutations in the YMDD (M204V/I) motif. One retrospective study suggested that the combination of tenofovir and lamivudine was associated with improved viral suppression compared with either agent alone (1051Jain MK, Comanor L, White C, et al. Treatment of hepatitis B with lamivudine and tenofovir in HIV/HBV-coinfected patients: factors associated with response. J Viral Hepat 2007;14:176-82.). Other studies also suggested that combination therapy reduces development of drug-resistant mutations (1034Marcellin P, Lau GK, Bonino F, et al. Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B. N Engl J Med 2004;351:1206-17., 1052Lampertico P, Vigano M, Manenti E, et al. Low resistance to adefovir combined with lamivudine: a 3-year study of 145 lamivudine-resistant hepatitis B patients. Gastroenterology 2007;133:1445-51.). For HIV-infected persons, certain specialists recommend combination therapy with two agents active against HBV to reduce the risk for HBV drug resistance, although no results from controlled trials exist to support this strategy (CII). Certain specialists recommend combination therapy with emtricitabine and tenofovir as part of an ART regimen because of ease of administration, tolerability, and dual HBV and HIV activity (CIII). Initiation of combination therapy also avoids the administration of sequential monotherapy, which can lead to multi-drug HBV resistance over time (1053Yim HJ, Hussain M, Liu Y, et al. Evolution of multi-drug resistant hepatitis B virus during sequential therapy. Hepatology 2006;44:703-12., 1054Rapti I, Dimou E, Mitsoula P, Hadziyannis SJ. Adding-on versus switching-to adefovir therapy in lamivudine-resistant HBeAg-negative chronic hepatitis B. Hepatology 2007;45:307-13.). The combination of lamivudine and pegIFN is not superior to pegIFN alone and is usually not recommended (1055Barbaro G, Zechini F, Pellicelli AM, et al. Long-term efficacy of interferon alpha-2b and lamivudine in combination compared to lamivudine monotherapy in patients with chronic hepatitis B: an Italian multicenter, randomized trial. J Hepatol 2001;35:406-11., 1056Schalm SW, Heathcote J, Cianciara J, et al. Lamivudine and alpha interferon combination treatment of patients with chronic hepatitis B infection: a randomised trial. Gut 2000;46:562-8.). The strategy of combination therapy versus monotherapy for treatment of HBV is being evaluated in a comparative clinical trial (1045Matthews GV, Dore GJ. Combination of tenofovir and lamivudine versus tenofovir after lamivudine failure for therapy of hepatitis B in HIV-coinfection. AIDS 2007;21:777-8.).

Entecavir also can be considered in patients with complete HIV suppression who do not demonstrate YMDD motif (M204V/I) mutations in HBV DNA (CIII). If entecavir is used in the presence of the M204V/I mutation, then careful monitoring of HBV DNA levels is indicated because of the increased risk for entecavir resistance in the presence of these pre-existing mutations.

Dual HBV and HCV infections are seen in 3%-5% of HIV-infected persons (1057Soriano V, Barreiro P, Martn-Carbonero L, et al. Treatment of chronic hepatitis B or C in HIV-infected patients with dual viral hepatitis. J Infect Dis 2007;195:1181-3.). The replication of one virus usually predominates over another; this phenomenon is referred to as "viral interference." A thorough laboratory evaluation to detect dual HBV and HCV coinfection should include HBV DNA and HCV RNA assays. Among patients infected with HBV, HCV, and HIV, consideration of ART should be the first priority. If ART is administered, then anti-HBV therapy must be included as part of the regimen (as above) and anti-HCV therapy can be introduced as needed. If ART is not desired, IFN-based therapy, which suppresses both HCV and HBV, should be considered (CIII). If IFN-based therapy for HCV has failed, treatment of chronic hepatitis B with nucleoside or nucleotide analogs is recommended (CIII).

Treatment of HBV in HIV-Infected Patients Who Are Not Receiving ART

For patients deferring therapy for HIV infection, agents with sole activity against HBV must be selected for treatment of chronic HBV infection (BIII). The lack of data regarding many of these agents in HIV/HBV-coinfected persons impedes firm treatment recommendations in this population. No data exist regarding the efficacy of pegIFN or the safety or efficacy of telbivudine in HIV-infected persons; adefovir has been evaluated in this population only in those with lamivudine-resistant HBV; and the clinical implications of entecavir-associated HIV resistance mutations prevent its use in this situation. Individualized therapy is necessary; however, certain guiding principles should be followed. The criteria for initiation of treatment for chronic HBV are the same for HIV-infected persons as for those with HBV monoinfection (CIII). Factors that might influence the choice of agent include the immune status of the patient, the level of hepatitis B viremia, and the patient's HBeAg status. For patients with CD4+ counts >350 cells/µL, adefovir or pegIFN alfa-2a monotherapy for 48 weeks might be considered, with close monitoring of HBV DNA levels and follow-up to evaluate for HBeAg seroconversion (CIII).

Duration of Anti-HBV Therapy

In HIV-seronegative patients, HBeAg seroconversions are sustained among approximately 80% of patients if lamivudine is continued 6-12 months after seroconversion. On the basis of data in HIV-uninfected persons, HIV/HBV-coinfected persons who are HBeAg positive and who become HBeAg negative and anti-HBe positive on lamivudine therapy should be treated for a minimum of 6-12 months beyond HBeAg seroconversion (BIII). All patients receiving ART should continue HBV therapy, even if they have seroconverted to anti-HBe (CIII).

Similar guidance on the duration of therapy can be applied to the use of other HBV active agents, with the exception of peg-IFN-based therapy, which is administered for a standard 48-week course. If HBeAg seroconversion does not occur but viral suppression has been achieved, treatment with anti-HBV agents, if tolerated, should be continued indefinitely (CIII).

Among HIV-seronegative, HBeAg-negative patients with chronic hepatitis B who are treated with lamivudine, ALT and HBV DNA levels might decline, but high rates of relapse have been reported when therapy is stopped (1058Tassopoulos NC, Volpes R, Pastore G, et al. Efficacy of lamivudine in patients with hepatitis B e antigen-negative/hepatitis B virus DNA-positive (precore mutant) chronic hepatitis B. Hepatology 1999;29:889-96.). Considering these findings, a majority of specialists would continue therapy indefinitely to achieve long-term HBV viral suppression (CIII).

Monitoring and Adverse Events, Including Immune Reconstitution Inflammatory Syndrome (IRIS)

Treatment response should be monitored by testing for HBV DNA and HBeAg at 3-month intervals and at 6-12-month intervals after stopping treatment. A virologic response is defined as a ≥2-log10 decrease in HBV DNA after 6 months of therapy. Ideally, the HBV DNA level after 6-12 months is <20-100 IU/mL based on a real-time PCR assay (1059Hoofnagle JH, Doo E, Liang TJ, Fleischer R, Lok AS. Management of hepatitis B: summary of a clinical research workshop. Hepatology 2007;45:1056-75.). A maintained virological response is a response that continues while on therapy, and a sustained virological response is one that is still present 6 months after stopping therapy. For patients who are HBeAg positive, loss of HBeAg is also a measure of virological response. Other markers that should be monitored and indicate treatment success include improvement in liver histology based on biopsy; normalization of serum aminotransferases; and, in those with loss of HBeAg, the development of anti-HBe. Sustained loss of HBsAg is considered by some to be a complete response; however, this desirable serologic response is uncommon (1060Lok AS, Heathcote EJ, Hoofnagle JH. Management of hepatitis B: 2000summary of a workshop. Gastroenterology 2001;120:1828-53.).

Major toxicities of IFN-alfa (pegylated or standard) include influenza-like symptoms (e.g., fever, myalgia, headache, and fatigue), neuropsychiatric abnormalities (e.g., depression, irritability, and cognitive dysfunction), cytopenias (e.g., thrombocytopenia, neutropenia, and reversible reduction in CD4+ count), retinopathy, neuropathy, and exacerbation of autoimmune disease. Depression might be severe enough to trigger suicide. Certain specialists recommend psychiatric evaluation before initiation of IFN-alfa for patients with a prior history of depression and frequent (monthly) monitoring for signs and symptoms of depression during treatment. Hypo- or hyperthyroidism, which is often irreversible, might occur 3-6 months after initiation of therapy with IFN-alfa. As a result, serum thyroid stimulating hormone (TSH) level should be monitored at baseline and periodically (e.g., every 3 months) for the duration of treatment. Depending on the severity of these toxicities and individual patient tolerance, side effects might be dose limiting or interfere with the ability to complete a course of treatment. IFN-alfa is contraindicated in patients with decompensated liver disease.

Adefovir causes renal tubular disease at doses of 30 mg/day or higher, but this toxicity is uncommon at the recommended 10 mg/day dose. Renal toxicity with tenofovir used solely for treatment of HBV has been reported rarely, although isolated cases of increased serum creatinine or renal tubular dysfunction have been observed, and might be more frequent in HIV-infected persons with underlying renal insufficiency or those treated for prolonged periods. Patients on either drug should have baseline urinalysis and creatinine monitoring. Periodic monitoring of serum creatinine and phosphate also should be done in patients receiving adefovir or tenofovir, especially those with underlying diabetes or taking other nephrotoxic agents, because they might be at increased risk for renal toxicity (1061Gallant JE, Parish MA, Keruly JC, Moore RD. Changes in renal function associated with tenofovir disoproxil fumarate treatment, compared with nucleoside reverse-transcriptase inhibitor treatment. Clin Infect Dis 2005;40:1194-8.).

When anti-HBV therapy with lamivudine, adefovir, or tenofovir is initiated, discontinuation is associated with a flare of liver disease in approximately 15% of cases, with loss of the benefit accrued from previous anti-HBV treatment (1062Honkoop P, de Man RA, Niesters HG, Zondervan PE, Schalm SW. Acute exacerbation of chronic hepatitis B virus infection after withdrawal of lamivudine therapy. Hepatology 2000;32:635-9.) and possible decompensation of liver disease. Even for patients not receiving ART, certain specialists recommend that when anti-HBV therapies are initiated, they should be continued unless contraindicated or unless the patient has been treated for 6-12 months beyond loss of HBeAg positivity (CIII). However, the risks and benefits of this practice are unknown. If anti-HBV therapy is discontinued and a flare occurs, anti-HBV therapy should be reinstituted because it can be potentially life saving (BIII).

Return of immune competence after ART (or after steroid withdrawal or chemotherapy) can lead to reactivation of HBV-associated liver disease. Any immune reconstitution can lead to a rise in serum aminotransferases, so called "hepatitis flare" (1063Lau GK. Does treatment with interferon-based therapy improve the natural history of chronic hepatitis B infection? J Hepatol 2007;46:6-8.), which constitutes IRIS in HIV/HBV-coinfected persons. IRIS might be manifested by dramatic increases in serum aminotransferases as CD4+ counts rise within the first 6-12 weeks after starting ART, with signs and symptoms characteristic of acute hepatitis. After introduction of ART, serum aminotransferases should be monitored closely; some experts recommend monthly for the first 3-6 months and then every 3 months thereafter (CIII). Any association between abnormal aminotransferases and clinical jaundice or synthetic dysfunction (elevated INR and low serum albumin) should prompt consultation with a hepatologist.

All patients with HBV and HIV must receive concomitant anti-HBV therapy when ART is used because these flares can be life threatening. Flares are worse in patients with more severe liver disease, especially cirrhosis. Distinguishing hepatotoxicity or other causes of hepatitis (acute HAV or acute HCV) from IRIS in this setting is difficult. When changing antiretroviral regimens, continuing agents with anti-HBV activity is important because of the risk for IRIS.

All classes of ARVs have been associated with hepatotoxicity as evidenced by substantial elevations in serum aminotransferases (1064Pol S, Lebray P, Vallet-Pichard A. HIV infection and hepatic enzyme abnormalities: intricacies of the pathogenic mechanisms. Clin Infect Dis 2004;38(Suppl 2):65-72.). ARV-associated hepatotoxicity might be dose dependent or idiosyncratic. The risk for hepatotoxicity has been consistently associated with elevated pre-ART aminotransferases and the presence of HBV or HCV coinfection (1065Kontorinis N, Dieterich D. Hepatotoxicity of antiretroviral therapy. AIDS Rev 2003;5:36-43., 1066Stern JO, Robinson PA, Love J, et al. A comprehensive hepatic safety analysis of nevirapine in different populations of HIV infected patients. J Acquir Immune Defic Syndr 2003;34(Suppl 1):1-33., 1067Sulkowski MS, Mehta SH, Chaisson RE, Thomas DL, Moore RD. Hepatotoxicity associated with protease inhibitor-based antiretroviral regimens with or without concurrent ritonavir. AIDS 2004;18:2277-84., 1068Sulkowski MS, Thomas DL, Chaisson RE, Moore RD. Hepatotoxicity associated with antiretroviral therapy in adults infected with human immunodeficiency virus and the role of hepatitis C or B virus infection. JAMA 2000;283:74-80., 1069Torti C, Lapadula G, Casari S, et al. Incidence and risk factors for liver enzyme elevation during highly active antiretroviral therapy in HIV-HCV co-infected patients: results from the Italian EPOKA-MASTER cohort. BMC Infect Dis 2005;14:58., 1070Martinez E, Blanco JL, Arnaiz JA, et al. Hepatotoxicity in HIV-1-infected patients receiving nevirapine-containing antiretroviral therapy. AIDS 2001;15:1261-8., 1071Meraviglia P, Schiavini M, Castagna A, et al. Lopinavir/ritonavir treatment in HIV antiretroviral-experienced patients: evaluation of risk factors for liver enzyme elevation. HIV Med 2004;5:334-43.,1072Saves M, Vandentorren S, Daucourt V, et al. Severe hepatic cytolysis: incidence and risk factors in patients treated by antiretroviral combinations. AIDS 1999;13:F115-21. ,1073Monforte V, Roman A, Gavalda J, et al. Nebulized amphotericin B prophylaxis for Aspergillus infection in lung transplantation: study of risk factors. J Heart Lung Transplant 2001;20:1274-81.). Despite the increased risk for hepatotoxicity in the setting of HCV or HBV coinfection, the majority of (80%-90%) coinfected patients do not have hepatotoxicity (1067Sulkowski MS, Mehta SH, Chaisson RE, Thomas DL, Moore RD. Hepatotoxicity associated with protease inhibitor-based antiretroviral regimens with or without concurrent ritonavir. AIDS 2004;18:2277-84.), and clinically significant hepatotoxicity is rare; aminotransferases return to baseline in the majority of cases, even if the offending medication is continued (1066Stern JO, Robinson PA, Love J, et al. A comprehensive hepatic safety analysis of nevirapine in different populations of HIV infected patients. J Acquir Immune Defic Syndr 2003;34(Suppl 1):1-33., 1074Sherman KE, Shire NJ, Cernohous P, et al. Liver injury and changes in hepatitis C Virus (HCV) RNA load associated with protease inhibitor-based antiretroviral therapy for treatment-naive HCV-HIV-coinfected patients: lopinavir-ritonavir versus nelfinavir. Clin Infect Dis 2005;41:1186-95.). Therefore, discontinuing ART is probably not necessary in the presence of hepatotoxicity unless the patient has symptoms of hypersensitivity (fever, lymphadenopathy, rash), symptomatic hepatitis (nausea, vomiting, abdominal pain, or jaundice), or elevations of serum aminotransferase levels >10 times the ULN. However, the development of jaundice is associated with severe morbidity and mortality and should trigger discontinuation of the offending drug(s) (1075Reuben A. Hy's law. Hepatology 2004;39:574-8.).

The major problem in managing adverse effects and drug-induced liver injury is determining which medication is the offending culprit and distinguishing drug toxicity from hepatic flares associated with IRIS. Close interaction of HIV clinicians and hepatologists is needed because liver histology might help to differentiate drug toxicity (e.g., eosinophils) from viral hepatitis (e.g., portal inflammation). Spontaneous HBV clearance can be associated with a flare, but occurs rarely in HIV-infected patients. Initiation of ART without anti-HBV therapy might lead to reactivation of HBV. A hepatic flare might also occur when patients must discontinue their ART. Although this should be discouraged, if ART must be discontinued for some reason, patients need to be counseled about the urgent need to continue HBV therapy but without any agents active against HIV to prevent inadvertent mono or dual anti-HIV drug selection pressure favoring development of HIV drug resistance. Elevated aminotransferases might also occur after the onset of drug resistance, which is common and increases over time with medications such as lamivudine (1037Benhamou Y, Bochet M, Thibault V, et al. Long-term incidence of hepatitis B virus resistance to lamivudine in human immunodeficiency virus-infected patients. Hepatology 1999;30:1302-6.). Serum HBV DNA testing will help determine if a flare of HBV has occurred. In this situation, HBV resistance testing should be undertaken in consultation with a specialist. Other causes of abnormal liver tests should be sought, including drugs, alcohol, viral hepatitis, and nonalcoholic fatty liver disease.

Management of Treatment Failure

Treatment failure is defined as the presence of HBV DNA greater than 1 log10 above nadir in a patient who is consistently adherent to therapy. Laboratory findings associated with treatment failure include persistent ALT elevations and persistently positive HBeAg for those who had detectable HBeAg at treatment onset.

In HIV-infected persons with lamivudine-resistant HBV, data from a case series of 35 HIV-HBV coinfected patients indicated that treatment with the combination of adefovir and continuation of lamivudine has substantial antiviral effect against lamivudine -resistant HBV (1076Benhamou Y, Bochet M, Thibault V, et al. Safety and efficacy of adefovir dipivoxil in patients co-infected with HIV-1 and lamivudine-resistant hepatitis B virus: an open-label pilot study. Lancet 2001;358:718-23.). Addition of either adefovir or tenofovir appears to lead to greater declines in HBV DNA in lamivudine-resistant coinfected patients (1041Peters MG, Andersen J, Lynch P, et al. Randomized controlled study of tenofovir and adefovir in chronic hepatitis B virus and HIV infection: ACTG A5127. Hepatology 2006;44:1110-6.). Flares of liver disease have been reported with development of resistance to lamivudine. The rate of development of lamivudine resistance is approximately 20% per year among HIV/HBV-coinfected persons treated with lamivudine (1037Benhamou Y, Bochet M, Thibault V, et al. Long-term incidence of hepatitis B virus resistance to lamivudine in human immunodeficiency virus-infected patients. Hepatology 1999;30:1302-6.). If lamivudine resistance is suspected or documented, tenofovir or adefovir should be added to lamivudine therapy (CIII). HBV DNA testing might be useful in this setting because increasing levels are associated with emergence of lamivudine resistance or relapse, and stable levels should suggest an alternative cause of acute deterioration. Patients receiving lamivudine who have no detectable HIV RNA, but do have detectable plasma HBV DNA, can be assumed to be lamivudine resistant. Treatment options for patients on ART who have lamivudine-resistant HBV, but fully suppressed HIV, include the addition of adefovir or pegIFN to lamivudine, or tenofovir can be exchanged for one of the nucleoside agents in the ART regimen (CIII). Persons with lamivudine-resistant HBV will have cross resistance to emtricitabine and telbivudine. In the setting of lamivudine-resistant HBV disease, either lamivudine or emtricitabine should be continued because this might decrease development of mutations to other anti-HBV drugs (CIII).

Treatment for ESLD among HIV/HBV-coinfected patients should be managed as it is in HIV-seronegative patients (BI). IFN-alfa is contraindicated in ESLD, but limited data indicate that lamivudine, adefovir, or tenofovir can be used safely (1037Benhamou Y, Bochet M, Thibault V, et al. Long-term incidence of hepatitis B virus resistance to lamivudine in human immunodeficiency virus-infected patients. Hepatology 1999;30:1302-6., 1077Lai CL, Chien RN, Leung NW, et al. A one-year trial of lamivudine for chronic hepatitis B. N Engl J Med 1998;339:61-8., 1078Dienstag JL, Schiff ER, Wright TL, et al. Lamivudine as initial treatment for chronic hepatitis B in the United States. N Engl J Med 1999;341:1256-63.). All patients with ascites should undergo paracentesis for analysis to verify that portal hypertension is the etiology and to exclude spontaneous bacterial peritonitis (SBP) (1079Runyon BA. Management of adult patients with ascites due to cirrhosis. Hepatology 2004;39:841-56.). Assessment of the serum-ascites albumin gradient (SAAG) is advisable; SAAG ≥1.1 mg/dL strongly suggests ascites secondary to portal hypertension. Management includes sodium restriction (>2 g/day) to alleviate fluid retention and diuretics. The recommended diuretic regimen is spironolactone alone or combined with furosemide (ratio of 40 mg furosemide: 100 mg spironolactone). Consideration should be given to primary prophylaxis against SBP with the administration of oral antibiotics such as norfloxacin (400 mg/day) or TMP-SMX (1 double-strength tablet/day) in those with an ascites total protein <1 g/dL (1080Singh N, Gayowski T, Yu VL, Wagener MM. Trimethoprim-sulfamethoxazole for the prevention of spontaneous bacterial peritonitis in cirrhosis: a randomized trial. Ann Intern Med 1995;122:595-8.). Secondary antibiotic prophylaxis is recommended for all persons with a history of SBP (AI).

Esophagogastroduodenoscopy (EGD or upper endoscopy) should be performed in all persons who progress to cirrhosis, particularly those with thrombocytopenia, at the time of diagnosis and then every 1-2 years to identify substantial gastroesophageal varices. For persons with varices, nonselective beta blockers (e.g., nadolol or propranolol) are the mainstay of both primary and secondary prevention of variceal hemorrhage; esophageal variceal ligation or banding is another preventive option, particularly for persons who cannot tolerate beta blockers. Hepatic encephalopathy, due to the accumulation of unmetabolized ammonia and other false neurotransmitters absorbed from the gut in the setting of liver dysfunction, might be subtle in early stages (916). Preventive measures include restriction of animal dietary protein consumption and the use of nonabsorbable disaccharides (e.g., lactulose) and/or antibiotics (e.g., neomycin, rifaximin).

Patients with HBV-related cirrhosis are at increased risk for HCC (1081Di Bisceglie AM. Hepatitis C and hepatocellular carcinoma. Hepatology 1997;26(Suppl 1):34-38.). Whether additional risk occurs in the setting of HIV infection is unclear (998Bruno R, Sacchi P, Filice C, Puoti M, Filice G. Hepatocellular carcinoma in HIV-infected patients with chronic hepatitis: an emerging issue. J Acquir Immune Defic Syndr 2002;30:535-6.). Although the optimal screening strategy to detect HCC is unknown, screening for HCC is recommended in patients with documented cirrhosis using hepatic ultrasound imaging performed at 6-12-month intervals (BIII) (1082Gebo KA, Chander G, Jenckes MW, et al. Screening tests for hepatocellular carcinoma in patients with chronic hepatitis C: a systematic review. Hepatology 2002;36(Suppl 1):584-92.). The utility of serum AFP for HCC screening in persons with HIV is unknown, and, because of poor specificity and sensitivity, results of AFP testing should be confirmed with liver imaging studies. In the absence of contraindications, HIV/HBV-coinfected persons with decompensated liver disease and/or early HCC are candidates for orthotopic liver transplantation because HIV infection is not a contraindication to organ transplantation with the use of effective ART (1083Miro JM, Laguno M, Moreno A, Rimola A. Management of end stage liver disease (ESLD): what is the current role of orthotopic liver transplantation (OLT)? J Hepatol 2006;44(Suppl 1):140-5.). Persons with cirrhosis should undergo periodic assessment of their liver disease status through the application of validated prognostic models (Child-Pugh-Turcotte [CPT] Score and Model for End-stage Liver Disease [MELD]) that predict mortality risk and are used to determine the medical need for liver transplantation (1084Forman LM, Lucey MR. Predicting the prognosis of chronic liver disease: an evolution from child to MELD (Mayo End-stage Liver Disease). Hepatology 2001;33:473-5.). Where feasible, coinfected persons with well-controlled HIV infection found to have liver decompensation (defined as CPT score ≥7 and/or MELD score >10) or evidence of early HCC should be referred for orthotopic liver transplantation (BIII). Because transplantation does not cure HBV infection, post-transplant HBV treatment is required (BIII).

Special Considerations During Pregnancy

Pregnant women, including HIV-infected women, should be screened for HBsAg. Those who are HBsAg negative and without antibody to hepatitis B should be offered vaccination against hepatitis B. This vaccination can be administered during pregnancy, preferably after the woman is on a stable ART regimen, to prevent the theoretical risk for HIV RNA rebound with vaccination. Treatment of symptomatic acute HBV infection during pregnancy should be supportive, with special attention given to maintaining blood glucose levels and normal clotting status. Risk for preterm labor and delivery might be increased with acute HBV infection.

Treatment of chronic HBV infection is usually not indicated in pregnancy (DIII), but HBV positivity must be taken into account when considering therapy options for the HIV-infected pregnant woman.

For women having indications for ART for their own health and expected to continue antiretrovirals postpartum, a regimen including two agents with activity against hepatitis B should be used (AIII) (1085CDC. Report of the NIH Panel to Define Principles of Therapy of HIV Infection and guidelines for use of antiretroviral agents in HIV infected adults and adolescents. MMWR 1998;47(No. RR-5).). Of the antiretroviral agents with activity against hepatitis B, the one most used in pregnancy is lamivudine. Approximately 1,800 cases of pregnancy outcomes after first-trimester exposure to lamivudine have been reported to the Antiretroviral Pregnancy Registry (APR) with no indication of an increased risk for birth defects after exposure (1086Committee Antiretroviral Pregnancy Registry. Antiretroviral Pregnancy Registry international interim report for 1 January 1989 through 31 July 2007. Wilmington, NC: Registry Coordinating Center, 2007.). Lamivudine has been well tolerated by pregnant women. Tenofovir was not teratogenic in animals, but reversible bone changes at high doses were seen in multiple animal species. A total of 266 cases of first-trimester exposure have been reported to the APR with no increase in birth defects noted (1086Committee Antiretroviral Pregnancy Registry. Antiretroviral Pregnancy Registry international interim report for 1 January 1989 through 31 July 2007. Wilmington, NC: Registry Coordinating Center, 2007.). Although tenofovir is not usually recommended as a first-line agent in pregnancy, in the setting of maternal chronic HBV infection, it can be included as the second agent with anti-HBV activity, in addition to lamivudine (BIII). Several other antiretroviral agents with activity against HBV, including emtricitabine, adefovir, and telbivudine, have been evaluated and not found to be teratogenic in animals, but experience with these agents in human pregnancy is limited. These agents could be included in a regimen during pregnancy if other options are not appropriate. Entecavir was associated with skeletal anomalies in rats and rabbits but only at high, maternally toxic doses. Data on use of entecavir in human pregnancy are not available. Cases of exposure during pregnancy to any of the antiretrovirals and HBV drugs listed should be reported to the Antiretroviral Pregnancy Registry (800-258-4263; http://www.apregistry.com). Interferons are not recommended for use in pregnancy, and ribavirin (RBV) is contraindicated in pregnancy. Although IFNs are not teratogenic, they are abortifacient at high doses in monkeys and should not be used in pregnant women because of the direct antigrowth and antiproliferative effects of these agents (1087Boskovic R, Wide R, Wolpin J, Bauer DJ, Koren G. The reproductive effects of beta interferon therapy in pregnancy: a longitudinal cohort. Neurology 2005;65:807-11.).

The choice of antiretroviral regimen for the pregnant woman with chronic HBV infection who requires antiretrovirals during pregnancy only for prevention of mother-to-child transmission (MTCT) and plans to discontinue therapy after delivery is more complex. Options include starting a triple therapy regimen including two agents with activity against HBV (as discussed above) but stopping therapy after delivery and monitoring closely for a flare of HBV activity, or using a regimen not including drugs active against HBV to avoid a potential flare when discontinued. As an alternative, if only short-term therapy is planned (e.g., starting in the third trimester), consideration should be given to using a combination antiretroviral regimen using lamivudine as the sole agent with activity against HBV (CIII). Certain specialists recommend the first option, using a regimen with dual HBV activity. This recommendation is made even when planning to discontinue postpartum because of the concern about potential IRIS-related flare of HBV activity during pregnancy, even among women with relatively high CD4+ counts, if ARV without anti-HBV activity is used. They believe that treating a potential flare in the postpartum period after discontinuing ARV is associated with less risk than treating an immune-mediated flare during pregnancy. In addition, using drugs with anti-HBV activity during pregnancy will lower HBV levels and potentially decrease the risk for failure of hepatitis B immune globulin (HBIG) and hepatitis B vaccine to prevent perinatal transmission of HBV, which is increased among women with high HBV DNA levels. Certain specialists would use an antiretroviral regimen without anti-HBV activity to avoid the possibility of flare when discontinued postpartum and to avoid the use of tenofovir, a drug with limited experience with long-term use in pregnancy. Certain specialists would use a highly active regimen that includes lamivudine as the only antiretroviral agent with activity against HBV, especially if starting the regimen later in pregnancy because of late care or delayed HIV diagnosis, to avoid use of tenofovir while still treating HBV. Decisions regarding choice of ARV regimen should be made taking into account CD4+ count, HIV RNA levels, time needed for chronic HIV therapy, HBV levels and indications for HBV therapy, gestational age when starting therapy, and patient preference.

Infants born to HBsAg-positive women should receive HBIG and hepatitis B vaccine within 12 hours of birth (AI). The second and third doses of vaccine should be administered at 1 and 6 months of age, respectively. This regimen is >95% effective in preventing HBV infection in these infants. Postvaccination testing for anti-HBs and HBsAg should be performed at age 9-15 months because of the infant's ongoing exposure to HBV.

TABLE 1. Prophylaxis to prevent first episode of opportunistic disease: Hepatitis B virus (HBV) infection
IndicationFirst choiceAlternative
Definitions of abbreviations: DS = double strength; PO = by mouth; SS = single strength; bid = twice daily; tiw = 3 times weekly; SQ = subcutaneous; IM = intramuscular
All HIV patients without evidence of prior exposure to HBV should be vaccinated with HBV vaccine, including patients with CD4+ count <200 cells/µL (AII)

Patients with isolated anti-HBc: (BII) (consider screening for HBV DNA before vaccination to rule out occult chronic HBV infection)


Vaccine non-responders: Defined as anti-HBs <10 IU/mL 1 month after a vaccination series

For patients with low CD4+ count at the time of first vaccination series, certain specialists might delay revaccination until after a sustained increase in CD4+ count with ART.
Hepatitis B vaccine IM (Engerix-B® 20 µg/mL or Recombivax HB® 10 µg/mL) at 0, 1, and 6 months (AII)

Anti-HBs should be obtained one month after completion of the vaccine series (BIII)

Revaccinate with a second vaccine series (BIII)
Some experts recommend vaccinating with 40 µg doses of either vaccine (CIII)







Some experts recommend revaccinating with 40 µg doses of either vaccine (CIII)
TABLE 2. Drug therapy for treatment and chronic maintenance therapy of AIDS-associated opportunistic infections in adults and adolescents: Hepatitis B virus (HBV) disease
Preferred therapy, duration of therapy, chronic maintenanceAlternative therapyOther options/issues
Therapy for patients who require ART
transparent gifgrey bulletPatients should be treated with agents active against both HIV and HBV or with agents with independent activity against each virus (CIII)
transparent gif
transparent gifgrey bulletConsider tenofovir + emtricitabine as part of HIV and HBV regimen (CIII)
transparent gif
Lamivudine or emtricitabine-nave patients
transparent gifgrey bullet[Lamivudine 150 mg PO bid (or 300 mg PO daily) or emtricitabine 200 mg PO daily] + tenofovir (TDF) 300 mg PO daily (CIII) (+ additional agent[s] active against HIV)
transparent gif
Lamivudine or emtricitabine-experienced patients with detectable HBV DNA (assume lamivudine-resistance)
transparent gifgrey bulletIf not on TDF: Add TDF 300 mg PO daily as part of an ART regimen + lamivudine or emtricitabine (CIII); or
transparent gif
transparent gifgrey bulletAdefovir 10 mg PO daily + lamivudine or emtricitabine + other combination ART (BII); or
transparent gif
transparent gifgrey bulletEntecavir 1 mg PO daily can be considered in patients with complete HIV suppression (while on ART) who do not demonstrate YMDD (M204V/I) motif mutations in HBV DNA (CIII)
transparent gif
Duration of therapy: Because of the high rates of relapse, certain specialists recommend continuing therapy indefinitely (CIII)
Treatment for patients who do not require ART
transparent gifgrey bulletUse agents with sole activity against HBV and with the least potential of selecting HIV resistance mutations (BIII)
transparent gif
transparent gifgrey bulletConsider early initiation of ART, especially for patients with high HBV DNA
transparent gif
For patients with CD4+ count >350 cells/µL, HBeAg (-), HBV DNA >2,000 IU/mL (>20,000 copies/mL)
transparent gifgrey bulletAdefovir 10 mg PO daily (CIII)
transparent gif



For patients with CD4+ count >350 cells/µL, HBeAg (+), HBV DNA >20,000 IU/mL (>200,000 copies/mL), and elevated ALT
transparent gifgrey bulletPeginterferon alfa-2a 180 µg SQ weekly (CIII) x 48 weeks - with careful follow-up of HBeAg conversion
transparent gif
Emtricitabine, entecavir, lamivudine, or tenofovir should not be used for the treatment of HBV infection in patients who are not receiving combination ART (EII)

Among patients coinfected with HIV, HBV, and HCV, consideration of starting ART should be the first priority. If ART is not required, an interferon-based regimen, which suppresses both HCV & HBV, should be considered (CIII)

If IFN-based treatment for HCV has failed, treatment of chronic HBV with nucleoside or nucleotide analogs is recommended (CIII)

Cross-resistance to emtricitabine or telbivudine should be assumed in patients with suspected or proven 3TC resistance

When changing ART regimens, continue agents with anti-HBV activity because of the risk of IRIS

If anti-HBV therapy is discontinued and a flare occurs, therapy should be reinstituted, as it can be potentially life saving (BIII)

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